6th Croucher-Pasteur Exchange Programme

Dr Marco VIGNUZZI (Virus Populations and Pathogenesis group, Institut Pasteur, Paris, France) gave a seminar on October 8, 2010 entitled: "New in vivo models to study the role of genetic diversity of RNA viruses in virus fitness and virulence"

Date: Friday, 8 October 2010

Time: 11:00 a.m.

Venue: Mrs Chen Yang Foo Oi Telemedicine Centre, 2/F, William M W Mong Block, Faculty of Medicine Bldg, 21 Sassoon Road, Pokfulam, Hong Kong

Abstract:

Recently, we described a high fidelity variant of poliovirus that generated fewer mutations and a more homogenous virus population (Vignuzzi et al., Nature 2006, Nat Med 2008). Whereas the consensus sequence of this population was the same as wild type, the mutant distribution was significantly different and correlated with an attenuated phenotype in a mouse model of infection. We hypothesize that RNA viruses evolved an optimal mutation frequency that permits maximum adaptability without compromising genetic identity. Indeed, mutage


nesis assays reveal that these viruses lie dangerously close to a maximal mutation threshold beyond which the virus is lethally mutagenized. Since the poliovirus mouse infection model does not permit natural infections, we have developed two new in vivo study models using the Coxsackie virus B3 and the Chikungunya virus.


In the Coxsackie virus model, we discovered new polymerase fidelity variants that generate higher or lower mutation frequencies than wild type. These variants have allowed us to identify a previously unknown mutagenic activity for amiloride compounds and they will permit population dynamic studies in vivo in mice.

In the Chikungunya virus model, passaging the virus population exclusively in vertebrate, or invertebrate cell lines, compared to alternating passages, has allowed us to show that arboviruses compromise their adaptability and evolvability by committing to this alternating host lifestyle. Furthermore, in vivo infection of mosquitoes has permitted us to identify key popula


tion bottlenecks that exert a severe selective pressure on the population.

Our most recent findings will be presented in the context of our previous research published on poliovirus to present the state of the art and big picture questions that remain to be addressed.